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Home > Topics > Emerging Issues > Vitamin A and PMTCT
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Vitamin A and the Risk of Mother-to-Child Transmission of HIV

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Introduction

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Vitamin A is the common name used for retinoids, a family of fat-soluble compounds that that play a crucial role in maintaining the integrity of the epithelial cells of the respiratory, urinary, and intestinal tracts as well as the surface lining of the eyes. Vitamin A also helps the skin and mucous membranes to act as a barrier to bacteria and viruses.( 1 )

The vitamin A family is divided into two general categories, depending on whether the retinoids come from an animal- or plant-based food source. Vitamin A obtained from animal-based foods such as milk and eggs is called preformed vitamin A and is absorbed in the form of retinol, one of the most active forms of vitamin A. Retinol also can be turned into retinal and retinoic acid (other active forms of vitamin A) in the body.( 1 ) Vitamin A obtained from brightly colored fruits and vegetables such as carrots and spinach is called provitamin A carotenoid. More than 500 types of carotenoids are found in foods, but only a few can be metabolized into the active retinoid; of these, beta-carotene is the most biologically active.

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Vitamin A Supplementation and Child Mortality and Morbidity

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Vitamin A has long been considered an antiinfective agent and, since its discovery early in the 20th century, it has become increasingly apparent that it plays an important role in vision, the regulation of cell growth, bone development, immune function, cell reproduction, and cell differentiation.( 1 , 2 ) Vitamin A deficiency causes night blindness and xerophthalmia, and it impairs the body's ability to fight infections.( 3 ) In children, low levels of vitamin A are strongly associated with an increased risk of respiratory and diarrheal infections, poor growth, and reduced likelihood of survival from serious illness.( 4 , 5 , 6 , 7 )

Vitamin A supplementation in children aged 6 months to 5 years in resource poor-countries who are prone to vitamin A deficiency has been shown to dramatically reduce rates of illness and death.( 8 , 9 ) The seminal study in this regard was a large community trial conducted in Aceh, Indonesia, which found that children >6 months of age who were given vitamin A supplements every 6 months had significantly lower mortality rates than those who received no supplements.( 10 ) These findings have been supported by several other large placebo-controlled trials conducted in populations that were presumed not to be HIV infected.( 8 ) Later studies have found that supplementation also may be beneficial for HIV-infected children.( 11 , 12 )

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Recommendations for Vitamin A Supplementation in Women and Children

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Because of the strong evidence of its efficacy, its low cost, and its feasibility, periodic vitamin A supplementation for children aged 6 months to 5 years has become a key health intervention in resource-poor countries recommended by the World Health Organization (WHO) and UNICEF. The WHO also recommends supplementation for children diagnosed with measles in communities where vitamin A deficiency is endemic and the death rate from measles is >1% (see Table 1).( 1 )

Vitamin A Supplementation Recommendations for Children (HIV Infected and Uninfected) ( 13 )
Children 6-59 months of age should receive vitamin A supplements every 4 to 6 months

  • 100,000 IU for infants 6-12 months
  • 200,000 IU for children >12 months


Table 1: Vitamin A Treatment Schedule during Measles: Children 0 to 59 Months of Age
Age First Dose
(Immediately on diagnosis)
Second Dose
(Next day)
0-5 months 50,000 IU (15 mg) 50,000 IU (15 mg)
6-11 months 100,000 IU (30 mg) 100,000 IU (30 mg)
12-59 months 200,000 IU (60 mg) 200,000 IU (60 mg)
Source : Pan American Health Organization. Providing Vitamin A Supplements through Immunization and Other Health Contacts for Children 6-59 Months and Women Up to 6 Weeks Postpartum: A Guide for Health Workers . Washington: Pan American Health Organization; 2001.
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Vitamin A supplementation for children <6 months of age is still of undetermined efficacy. A trial conducted in Peru, India, and Ghana, in which mothers received 200,000 IU of vitamin A postpartum and infants received 25,000 IU of vitamin A during routine immunization (at approximately 6, 10, and 14 weeks), found that supplementation had no effect on infant mortality.( 14 ) A study of infants in India who received a high dose (48,000 IU) of vitamin A 2 days after birth found a 22% decrease in mortality during the first 6 months of life; however a randomized, placebo-controlled study conducted in Zimbabwe in which infants received 50,000 IU of vitamin A and mothers received 400,000 IU of vitamin A within 96 hours of delivery showed no reduction in infant mortality.( 15 , 16 )

Vitamin A Supplementation Recommendations for Pregnant and Lactating Women (HIV Infected and Uninfected) ( 13 , 17 , 18 )

Because many pregnant women also suffer from vitamin A deficiency, the WHO currently recommends the following:

  • A single large postpartum dose of vitamin A of 200,000 IU should be given to women in areas where prevalence of vitamin A deficiency is high.
  • This dose for the mother should be given as soon as possible after delivery (not later than 6-8 weeks after delivery).
  • The daily vitamin A intake during pregnancy and lactation should not exceed the recommended daily allowance (RDA).

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Vitamin A and HIV: Early Studies

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Because of this strong evidence of the important role played by vitamin A in maintaining immune function, it was logical that researchers would explore its potential for controlling HIV disease progression and reducing transmission. Several in vitro studies conducted in the 1990s found that HIV-infected cells treated with vitamin A had slower rates of viral replication.( 19 , 20 ) However, other cell culture studies had contrary findings. In humans, very low and very high levels of vitamin A were found to be linked to disease progression and complications.( 21 , 22 , 23 )

Regarding mother-to-child transmission (MTCT) of HIV, there were several ways in which vitamin A was thought to influence vertical transmission. Some investigators thought that vitamin A levels could influence clinical, immunological, or viral disease progression among pregnant women. This hypothesis was supported by several studies conducted in the late 1990s that found an association between low serum retinol levels and HIV shedding in genital tract secretions and breast milk.( 24 , 25 , 26 ) Another hypothesis was that vitamin A supplementation might reduce the risk of vertical transmission by improving or maintaining the integrity of the epithelial lining of the placenta, the mother's genital tract, or breasts. Yet, others thought that low levels of maternal vitamin A could increase the risk of prematurity and low birth weight, which in turn were thought to be risk factors for transmission.

Observational studies conducted in the 1990s seemed to support these theories. These studies found strong associations between low serum levels of vitamin A in HIV-infected patients and both advanced HIV disease and higher risk of MTCT. A study of 338 HIV-infected pregnant women in Malawi found that the MTCT rate was 32% in women with low serum retinol levels (<0.70 µmol/L), compared with only 7% in women with normal serum retinol levels (>1.40 µmol/L) (p < .0001).( 27 ) This strong linear inverse relationship between MTCT rates and serum retinol levels persisted after controlling for baseline maternal age, body mass index, and CD4 cell count. Researchers also found an inverse relationship between maternal serum retinol levels and infant mortality rates.( 28 )

A 1997 study conducted in two cities in the United States found similar relationships between maternal serum retinol and MTCT of HIV. Women with serum retinol of <0.70 µmol/L were 5 times more likely to transmit HIV to their offspring than those with adequate retinol levels, after controlling for CD4 cell percentage, gestational age, duration of membrane rupture, and mode of delivery.( 29 ) However, two other observational studies in the United States showed no association between MTCT rates and vitamin A deficiency.( 30 , 31 ) It is worth noting that these early studies used different definitions for vitamin A deficiency.( 32 )

Because serum retinol levels may decline in the presence of HIV infection, it was difficult to draw conclusions from the correlations between MTCT rates and low serum retinol levels found in these early observational studies.( 33 ) Although the studies did attempt to control for HIV disease stage as a confounding factor, other potential confounders such as socioeconomic factors could account for the observations. For example, it is posited that low serum retinol could be a marker of other micronutrient deficiencies that may affect MTCT rates. The presence of other infections secondary to gastrointestinal disease and malabsorption also may explain the correlation. Randomized controlled trials to examine the effect of vitamin A on HIV transmission would be needed before definitive recommendations could be made on its use as a preventative measure.

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Randomized Trials on the Effect of Vitamin A Supplementation on MTCT of HIV

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Overview

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Several such large micronutrient supplementation trials have been conducted over the past 10 years among pregnant, HIV-infected women in sub-Saharan Africa to further explore the possible relationship between vitamin A and vertical transmission of HIV. The most significant trials were conducted in South Africa, Malawi, Tanzania, and Zimbabwe.

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Durban, South Africa

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The Durban study, conducted at the University of Natal in South Africa, randomized 728 HIV-infected pregnant women to receive either a placebo or 5,000 IU of vitamin A (retinyl palmitate) and 30 mg of beta-carotene once a day during the third trimester of pregnancy and 200,000 IU of vitamin A (retinyl palmitate) after delivery. Women in the study received no antiretroviral prophylaxis or treatment; most chose not to breast-feed.

At 3 months postpartum, investigators found no difference in MTCT rates between the vitamin A and placebo groups (20.3% vs 22.3%). Whereas vitamin A supplementation reduced the risk of preterm delivery (11.4% in the vitamin A group vs 17.4% in the placebo group; p = .03), it had no effect on infant death: At 12 months, infant mortality was 9.3% in the vitamin A group vs 10.0% in the placebo group.( 34 ) There was a trend for preterm babies whose mothers had received antepartum vitamin A to have lower rates of HIV infection than those whose mothers were in the placebo group, but this association was not statistically significant.

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Blantyre, Malawi

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In the study conducted by Kumwenda et al in Blantyre, Malawi, 697 HIV-infected pregnant women were randomized to receive either placebo or a daily supplement of vitamin A (10,000 IU), beginning at 18-28 weeks of gestation until delivery. Mothers in both arms of the study also received daily iron and folate supplements from enrollment until delivery as well as 100,000 IU of vitamin A at 6 weeks postpartum in accordance with the Malawi Ministry of Health guidelines.( 35 )

As was the case in South Africa, the investigators in Malawi found that daily supplementation with vitamin A had no significant effect on MTCT rates:

  • At 6 weeks, the transmission rate was 26.6% in the vitamin A arm vs 27.8% in the placebo arm (p = .76).
  • At 12 months, the transmission rate was 27.3% in the vitamin A arm vs 32.0% in the placebo arm (p = .25).
  • At 24 months, the transmission rate was 27.7% in the vitamin A arm vs 32.8% in the placebo arm (p = .21).
  • Vitamin A significantly reduced the risk of low birth weight and infant anemia at 6 weeks.( 35 )

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Dar es Salaam, Tanzania

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The results of the studies in South Africa and Malawi were somewhat discouraging but consistent, suggesting that, even though vitamin A supplementation did not decrease transmission rates, it significantly improved birth outcomes and did not increase the likelihood of HIV transmission. This consensus was upset by a series of reports from an ongoing large randomized trial conducted in Dar es Salaam, Tanzania, which found that vitamin A supplementation could increase the risk of HIV transmission from mother to infant through breast-feeding. The interventions of the 4-arm, randomized, placebo-controlled trial are outlined in the table below.( 36 , 37 )


Table 2: Multivitamin Study Interventions (Dar es Salaam, Tanzania)
ANTEPARTUM INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT
Arm 1: Starting at 12-28 weeks' gestation:

Daily vitamin A (5,000 IU + 30 mg beta-carotene)
Single-dose vitamin A (200,000 IU) During lactation:

Daily vitamin A (5,000 IU + 30 mg beta-carotene)
Vitamin A 100,000 IU at 6 months, then 200,000 IU every 6 months thereafter
Arm 2: Daily multivitamin* Placebo Daily multivitamin*
Arm 3: Daily vitamin A (5,000 IU + 30 mg beta-carotene)

plus

Multivitamin
Single-dose vitamin A (200,000 IU) Daily vitamin A (5,000 IU + 30 mg beta-carotene)

plus

Multivitamin
Arm 4: Placebo Placebo Placebo
All Mothers Daily doses of ferrous sulfate (400 mg, equivalent to 120 mg ferrous iron), folate (5 mg), and weekly doses of prophylactic chloroquine phosphate
Neither mothers nor infants received antiretroviral prophylaxis.
Source : Mofenson L. Overview of Perinatal Intervention Trials. San Francisco: UCSF Center for HIV Information; September 20, 2006.
* Multivitamins: 20 mg B1, 20 mg B2, 25 mg B6, 100 mg niacin, 50 µg B12, 500 mg C, 30 mg E, and 0.8 mg folic acid
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Tanzania Results

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Multivitamin supplementation

Multivitamin supplementation did not have a significant effect on antepartum, intrapartum, or postpartum HIV transmission. It also did not affect 24-month infant mortality rates. However, multivitamin supplementation did seem to reduce HIV transmission and infant mortality in a subset of women who were nutritionally and immunologically compromised mothers (those who were anemic and those who had high erythrocyte sedimentation rates or low CD4 cell counts). Multivitamin supplementation also seemed to have positive effects on the health outcomes of women and their children: It reduced the rates of progression to AIDS in HIV-infected women postpartum, reduced developmental delays in infants' motor skills on the Bayley Scales of Infant Development, and increased psychomotor development index scores by a mean 2.6 points. However, it did not increase the mental development index scores of infants.( 38 , 39 )

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Vitamin A supplementation

Unlike the studies conducted in South Africa and Malawi, the Tanzanian study provided daily vitamin A and beta-carotene supplements during breast-feeding. It was supplementation provided during this period that specifically seemed to be risky. Vitamin A supplementation had no effect on antepartum or intrapartum transmission or on infant mortality. However, it did increase postpartum HIV transmission through breast-feeding. At 24 months, the rate of MTCT in infants whose mothers were randomized to receive vitamin A had increased by 38% (34.2% in those receiving vitamin A vs 25.4% in those receiving no vitamin A [p = .009; relative risk: 1.38; 95% confidence interval: 1.09, 1.76]). Other data from the study suggested that daily vitamin A supplementation increased viral shedding in the lower genital tract.( 43 )

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Harare, Zimbabwe

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It was hoped that the ZVITAMBO (Zimbabwe Vitamin A for Mothers and Babies) study, which is the largest study to date on the effect of vitamin A on MTCT, would clarify the discrepant results seen in the studies discussed above. Unlike the previous studies, which looked at the effects of daily supplementation, this study examined the effect of simpler, single-dose regimens (400,000 IU vitamin A for the mother shortly after delivery; 50,000 IU vitamin A for the baby). The study enrolled a total of 14,110 mother-infant pairs within 96 hours of delivery, of which 4,495 infants born to HIV-positive women could be included in the study. These mothers and their infants were randomized to 4 arms as outlined in the table below.( 40 )


Table 3: ZVITAMBO Study Interventions
INTRAPARTUM POSTPARTUM MOTHER POSTPARTUM INFANT
Arm 1: If identified early enough in labor:

Single-dose NVP 200 mg
Single-dose vitamin A 400,000 IU Single-dose vitamin A 50,000 IU

NVP 2 mg/kg x 1 at 48 hours
Arm 2: Single-dose vitamin A 400,000 IU Placebo

NVP 2 mg/kg x 1 at 48 hours
Arm 3: Placebo Single-dose vitamin A 50,000 IU

NVP 2 mg/kg x 1 at 48 hours
Arm 4: Placebo Placebo

NVP 2 mg/kg x 1 at 48 hours
Abbreviations: NVP = nevirapine
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Researchers also tracked the timing of HIV infection in the infants (antepartum, intrapartum, or postpartum) and explored whether the timing of infection was affected by supplementation and whether mortality and morbidity outcomes were different for infants infected at different times. All but 4 mothers in the study breast-fed their infants.

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ZVITAMBO Results

The ZVITAMBO study found that neither maternal nor neonatal vitamin A supplementation significantly affected MTCT or infant mortality between baseline and 24 months. During this period, vitamin A supplementation did not reduce rates of MTCT or infant mortality.

However, looking at mortality rates based on when infants became infected, researchers found that the timing of infant infection modified the effect that vitamin A had on mortality and MTCT rates. In subsets of infants, vitamin A supplementation for the mother or the infant increased infant mortality.( 40 )

  • Among infants who were uninfected at baseline, mortality was not affected by vitamin A supplementation for either mother or child.
  • Among infants uninfected at birth who became infected in the first 6 weeks of life, vitamin A supplementation to the infant reduced mortality by 28% (p = .01), but maternal supplementation had no effect.
  • Among infants who remained uninfected at 6 weeks of life, vitamin A supplementation for either the mother or the child almost doubled the mortality rate (p =< .05).
  • Among infants born to HIV-infected mothers, MTCT rates and infection-or-death rates tended to be higher for those in arms 2 and 3 of the study (vitamin A supplementation for the mother but not the infant, or supplementation for the infant but not the mother) but, strangely, this was not the case for infants in arm 1 (vitamin A supplementation for both the mother and the child).
  • At 12 months, HIV-free survival rates were significantly reduced for infants in arms 2 and 3 of the study but not for infants in arm 1.
  • By 24 months, differences in infant mortality rates among the different arms of the study had faded.

Vitamin A supplementation did not affect maternal mortality or rates of hospitalization or overall number of clinic visits for illness for mothers.( 41 )

The authors explain the disturbing increase in infant mortality in arms 2 and 3 of the study by suggesting that "priming" the infants and mothers with vitamin A increased the viral load in those who became infected during breast-feeding, "thereby hastening their progression to death."( 40 ) The higher rates of MTCT seen in arms 2 and 3 but not arm 1 are mysterious, and the study authors state that they are probably due to chance. However, it does not seem prudent to dismiss these findings because they could perhaps explain the high mortality found in all infants exposed to vitamin A who were infected postnatally.

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Discussion

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Rather than clarify the situation, the results from ZVITAMBO highlight the complexity of the unknown interactions among vitamin A, immune system function, and HIV. The cause of the discrepancies found in various studies is not clear. Some may be attributable to the differences in the various vitamin A regimens used in the studies, variations in the dosages administered, or differences in the duration of supplementation.( 42 ) For example, in Malawi and South Africa, vitamin A supplements were given daily during the prenatal period only; in Tanzania, vitamin A was given from recruitment through pregnancy and lactation. In Zimbabwe, it was given only once, shortly after delivery. In addition, some trials provided vitamin A supplementation to all participants at some point during the study; in Malawi, all mothers received 100,000 IU of vitamin A at 6 weeks postpartum, and in Tanzania all infants received 100,000 IU at 6 months and then 200,000 IU every 6 months thereafter.

Baseline serum retinol levels also differed greatly among the various studies. For example, the women in the Malawi study had lower baseline serum retinol levels than the women in South Africa, Tanzania, and Zimbabwe.( 42 )


Table 4: Mean Serum Retinol Level among HIV-Infected Women in Key MTCT Studies
Study Mean Serum Retinol Level
(HIV-Infected Women)
Malawi 0.72 µmol/L
South Africa 0.95 µmol/L
Tanzania 0.90 µmol/L
Zimbabwe 0.98 µmol/L (SD 0.35 µmol/L)
Abbreviation: SD = standard deviation
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It is also speculated that other factors in the study such as the addition of iron supplements in Tanzania and South Africa or malaria prophylaxis in Tanzania could have modified the effect of vitamin A.( 42 )

However, these differences do not seem significant enough to explain the inconsistencies of the various study findings. Rather, the Tanzania and Zimbabwe studies seem to suggest that vitamin A supplementation may increase susceptibility to HIV infection through breast milk, perhaps by affecting viral load in breast milk. Other research approaches such as metaanalysis may be needed to determine the relationship between vitamin A and HIV transmission through breast milk before specific recommendations can be made regarding supplementation for women in areas were HIV is endemic.

The inconsistencies among the results of randomized controlled studies and the early observational studies that found associations between low serum retinol levels and MTCT rates highlight the importance of exercising caution in interpreting these results. Observational studies have a high potential for confounding, and micronutrient interventions for HIV-infected patients are particularly confounding because serum levels of micronutrients such as vitamin A may be correlated with HIV disease progression or an acute-phase response.

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Take-Home Points

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Although the implications of the findings of the several randomized control trials on vitamin A supplementation and MTCT are not definitive, taken together, we can draw some conclusions to guide clinical practice:

  • Vitamin A supplementation, whether given as daily doses during pregnancy and lactation or a as a single dose postpartum, does not reduce the rate of mother-to-child transmission of HIV. There is no evidence to support the use of vitamin A for this purpose.
  • Vitamin A supplementation for HIV-infected children may prolong their survival.
  • Vitamin A supplementation for women in the postnatal period has been associated with a significant increase in risk of HIV transmission through breast-feeding in Tanzania. In Zimbabwe, vitamin A supplementation to either the mother or child doubled mortality in children who were infected after 6 weeks of life.
  • Taken together, these findings suggest that, in areas with high HIV prevalence, the risks of universal maternal or neonatal vitamin A supplementation may outweigh the benefits and this intervention should be implemented with caution.
  • If the decision is made to implement vitamin A supplementation, the WHO guidelines should be followed closely: The daily vitamin A intake during pregnancy and lactation should not exceed the RDA. In areas where vitamin A deficiency is endemic, a single high dose of vitamin A (200,000 IU) is recommended for women as soon as possible after delivery and not later than 6-8 weeks after delivery.( 17 , 18 )
  • Additional large controlled studies or metaanalysis may be required before further recommendations on the subject can be made.

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References

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